Evaluation of Bovine Milk Extracellular Vesicles for the Delivery of Locked Nucleic Acid Antisense Oligonucleotides


Authors: P. Grossen, M. Portmann, E. Koller, M. Duschmalé, T. Minz, S. Sewing and M. Keller et. al.

Journal: European Journal of Pharmaceutics and Biopharmaceutics

DOI: 10.1016/j.ejpb.2020.11.012

Publication - Abstract

November 26, 2020

siRNA Other Applications Other Formulations

Abstract

The natural capacity of extracellular vesicles (EVs) to transport their payload to recipient cells has raised big interest to repurpose EVs as delivery vehicles for xenobiotics. In the present study, bovine milk-derived EVs (BMEVs) were investigated for their potential to shuttle locked nucleic acid-modified antisense oligonucleotides (LNA ASOs) into the systemic circulation after oral administration. To this end, a broad array of analytical methods including proteomics and lipidomics were used to thoroughly characterize BMEVs. We found that additional purification by density gradients efficiently reduced levels of non-EV associated proteins. The potential of BMEVs to functionally transfer LNA ASOs was tested using advanced in vitro systems (i.e. hPSC-derived neurons and primary human cells). A slight increase in cellular LNA ASO internalization and target gene reduction was observed when LNA ASOs were delivered using BMEVs. When dosed orally in mice, only a small fraction (about 1% of total administered dose) of LNA ASOs was recovered in the peripheral tissues liver and kidney, however, no significant reduction in target gene expression (i.e. functional knockdown) was observed.

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